Epilepsy Care in the Real World of Multiple Medical Considerations

Abstract

Similar to the general population, people with epilepsy (PWE) will often have multiple medical issues that may impact their care. It is therefore important for epilepsy clinicians to be aware of these issues to optimize treatment and quality of life outcomes. In this review, we discuss cardiovascular and respiratory as well as infectious disorders in PWE. We also examine autoimmune disorders and outline reproductive and sexual health issues.

Introduction

Patients with epilepsy (PWE) like other individuals in society often have other medical conditions that they receive care for. Well-established co-morbidities include depression and anxiety, migraines as well as cognitive dysfunction and learning disabilities. Other co-morbidities (prevalence ratios within parenthesis) include heart disease (2.3), hypertension (1.9), stroke (7.0), diabetes (1.6), asthma (1.8), Chronic Obstructive Pulmonary Disease (2.9), arthritis (2.3), back pain (1.5), fibromyalgia (2.0), and alcohol use disorder (4.4). ¹ In adults, the prevalence of epilepsy is slightly higher in men as compared to women, with higher prevalences in the midlife cohort (40-59 years), and at lower income levels. Prevalence is not specifically increased in any one racial or ethnic group. ² Social determinants of health (SDOH) play an important role in the lives of people with epilepsy. SDOH can be classified into social-economic status (including social class, occupation, education, immigration status, and income), epilepsy care (includes access, insurance, and consistency), material conditions (housing, schools, employment, diet, neighborhood, and mobility), social capital (information networks), psychosocial factors (self-perception and stigma), and political contexts (public policy and care regulation, anti-discrimination laws, media campaigns, advocacy, and social values). ³ This review summarizes common conditions that co-exist with epilepsy and reviews pharmacological interactions between medications to treat other medical issues and anti-seizure medications (ASM). It is important to recognize both common and emerging health conditions in the context of epilepsy care. We will also address the influence of gender and sexual health factors in epilepsy care and examine epilepsy care in the setting of multiple medical co-morbidities.

Epilepsy and Infectious Respiratory Diseases

The recent Coronavirus disease (COVID-19) pandemic has highlighted the need to review how respiratory infections can affect the management of epilepsy and seizures. Neurotropic respiratory pathogens may cause various neurologic manifestations that include seizures, status epilepticus, and even epilepsy. Seizures may be triggered by various infection-related factors such as high fevers, sleep deprivation, and metabolic changes. In the case of COVID-19 caused by the respiratory virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), studies suggest that the incidence of new-onset seizures or epilepsy linked to COVID-19 is higher than that associated with influenza, although the absolute risk remains low (around 1%). ⁴

Patients with epilepsy may face heightened risks for severe illness and loss of seizure control for several reasons. Antimicrobials, like beta-lactams, and over-the-counter (OTC) medications, like antihistamines, are frequently used to treat respiratory infections, and their symptoms are known to have the potential to increase the risk of seizures. ⁵ Some may require immunosuppressive treatment in the management of their epilepsy, increasing their risk of severe infections and reduced vaccine efficacy. ⁶ The use of ASM like gabapentinoids and benzodiazepines can exacerbate the risk of respiratory depression, further complicating the management of infections. In general, pharmacokinetic (PK) changes during infections can alter the absorption, distribution, metabolism, and excretion of ASM, potentially reducing their efficacy and leading to inadequate seizure control. ⁶ Moreover, these PK changes may also increase the risk of ASM-related toxicity complicating epilepsy management.

It is essential to review drug interactions with the patient's current ASM upfront when selecting antimicrobial and antiviral therapies.^6,7 Fortunately, there are several reliable drug interaction screening tools that can assess interactions with antimicrobial and antiviral treatments, including antivirals specific for COVID-19 (COVID-19 Drug Interactions, University of Liverpool). ⁸ The American Epilepsy Society has published an updated tabular summary of commonly used ASMs available in the U.S., serving as a quick reference for their PK interactions. ⁹ Including prescription symptomatic therapies, such as codeine-based antitussives, and OTC medications like dextromethorphan is crucial, as significant interactions may occur even with newer ASM, affecting treatment efficacy and increasing side effects.

Preventing infection is vital to mitigating the risk of seizure exacerbation and severe illness. Thus, managing epilepsy includes infection prevention and hygiene strategies, that incorporate immunization against vaccine-preventable diseases such as influenza, COVID-19, and respiratory syncytial virus. ¹⁰ Vaccine hesitancy among PWE often arises from fears of vaccines exacerbating seizures. ¹¹ This concern is particularly relevant given the variable COVID-19 vaccination rates in PWE (ranging from 17% to 70%) as the world adjusts to the endemic phase of the virus.^12,13 Importantly, data shows that exacerbations of seizures from immunization with COVID-19 vaccines, like most vaccines, are uncommon for most PWE. ¹⁴ However, a small subset of individuals may experience vaccine-related neurologic complications, emphasizing the need for careful evaluation of contraindications and patient education regarding potential side effects.^10,14

Epilepsy and Chronic Cardiovascular and Metabolic Diseases

Seizures have been associated with catecholamine surges and hypoxemic damage to the cardiovascular system, leading to the “Epileptic Heart Syndrome.” ¹⁵ Adding to that are the adverse vascular effects of enzyme-inducing ASM (EIASM) and their drug-drug interactions. EIASM treatment bears a higher hazard of incident cardiovascular disease ¹⁶ and higher mortality among poststroke patients with epilepsy. ¹⁷ No increased risk of thromboembolic events was found in patients treated with direct oral anticoagulants (DOAC) and EIASMs versus noninducing ASMs. ¹⁸ However, additional anticoagulants were used more commonly among patients exposed to EIASMs compared with controls.

To minimize the impact of ASMs on the course of cardiovascular and metabolic diseases, it is important to consider the differences between them and within other drug classes. For instance, atorvastatin and simvastatin were the statins most commonly prescribed for noninstitutionalized civilians ¹⁹ but are also the statins most sensitive to enzyme induction. ²⁰ Eslicarbazepine acetate has more modest effects than carbamazepine on the pharmacokinetics of other drugs yet decreases the exposure to simvastatin by one-half at a less-than-maximal dose. ²¹ All calcium channel blockers, particularly felodipine and nisoldipine, are affected by EIASM. ²⁰ Dabigatran exposure is not predicted to be considerably affected by low or moderate doses of oxcarbazepine, eslicarbazepine acetate, clobazam, or rufinamide. However, DOAC combinations with strong EIASMs are contraindicated and cenobamate dosage in DOAC-treated patients should not exceed 100 mg/day. ²² Together, these data suggest that even moderate inducers should be used with caution in patients with cardiovascular disease.

In addition to enzyme induction, treatment with carbamazepine, eslicarbazepine acetate, and particularly oxcarbazepine can lead to hyponatremia. Special caution is required in the elderly and in those treated with diuretics. ²³ Caution is also advised with sodium channel blockers in patients with cardiac conduction abnormalities or with severe cardiac disease and in people older than 60 years.^24,25

The recently introduced glucagon-like peptide (GLP)-1 inhibitors (eg, semaglutide) delay gastric emptying and reduce gastric acid secretion. Their drug-drug interactions are usually not clinically significant. However, increased clinical or laboratory monitoring is advised for narrow therapeutic index drugs whose absorption might increase, especially carbamazepine and phenytoin.^26,27 Weight loss itself may enhance the elimination of ASMs whose metabolism is largely mediated by cytochrome P450 3A4,^26,28 such as carbamazepine, everolimus, and perampanel, potentially leading to loss of seizure control.

Epilepsy and Autoimmune Diseases

The intersection of epilepsy and autoimmune diseases represents a rapidly evolving area of research, offering new insights into the mechanisms underlying these conditions.^29,30 Recent findings have highlighted the growing recognition of autoimmune seizures and epilepsies, emphasizing advancements in diagnostic tools and therapeutic strategies that are reshaping modern epilepsy care. ³⁰ By exploring autoantibody and cytokine profiles, researchers are uncovering critical links between immune dysfunction and epilepsy.

Autoimmune diseases have been demonstrated to substantially elevate the risk of epilepsy, especially in children. ³¹ However, in systemic autoimmune disorders, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), seizures are frequently attributed to secondary conditions like stroke or metabolic dysfunction, rather than autoimmune encephalitis. ³² These findings highlight the association between systemic autoimmunity and seizure risk, but in many of these cases, central nervous system inflammation might not be the primary cause. This underscores the necessity of considering other underlying comorbidities.

Central to understanding autoimmune seizures/epilepsy is the role of neural-specific autoantibodies. Various distinct cell-surface antibodies, including leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and N-methyl-D-aspartate receptor (NMDA-R) antibodies, along with intracellular antibodies such as glutamic acid decarboxylase 65 (GAD65) and antineuronal nuclear autoantibody type 1 (ANNA1), have been associated with seizure presentations.^30,33 LGI1 IgG-associated seizures/encephalitis typically occur in older males and are characterized by unique seizure semiologies, such as faciobrachial dystonic seizures, ictal bradycardia, or pilomotor seizures. ³⁴ In contrast, CASPR2 antibodies are often found in focal-onset seizures that are accompanied by episodic ataxia or emotional instability.^34,35 Myelin oligodendrocyte glycoprotein (MOG) antibodies, often seen in pediatric cases of cerebral cortical encephalitis or acute disseminated encephalomyelitis, are associated with self-limited seizures, ³⁶ and GAD65 antibodies are linked to chronic epilepsy with early onset that often proves resistant to standard antiseizure therapies as well as immunotherapies. ³⁷ These biomarkers have proven pivotal in enhancing the recognition of autoimmune seizure presentations, as evidenced by the increased incidence of autoimmune encephalitis in the last decade. ³⁸ They have also played an important role in developing biomarker-specific treatment approaches, which require further refinement and evaluation through randomized controlled trials.

Innovative diagnostic tools are also transforming the landscape of autoimmune epilepsy. High-throughput platforms like Phage ImmunoPrecipitation Sequencing (PhIP-Seq), protein microarray, and Molecular Indexing of Proteins by Self-Assembly (MIPSA) are enabling the discovery of novel autoantibodies which may provide new avenues for diagnosis.^39–41 However, thorough validation of these biomarkers, development of clinical tests with the highest specificity, and selection of appropriate patients for autoantibody evaluation are critical to limit false positives. Furthermore, a cautious approach is necessary when interpreting results, as low-titer antibodies or mismatched clinical syndromes can lead to misdiagnosis.

The treatment of autoimmune seizures and epilepsy is largely dependent on the administration of immunotherapy.^30,42 A structured therapeutic approach begins with first-line treatments, such as high-dose corticosteroids, intravenous immunoglobulin (IVIg), or plasma exchange (PLEX). Often for cases at risk of disease relapse/progression or refractory cases, the addition of rituximab, mycophenolate mofetil, or cyclophosphamide is considered. Early immunotherapy, informed by autoantibody profiles, has been shown to improve long-term seizure control and quality of life. ⁴²

There is a pressing need for multicenter trials to enhance therapeutic strategies for autoimmune seizures/epilepsy. Emerging biomarkers and therapies offer hope for improving outcomes, but it is important to evaluate their efficacy through well-designed clinical trials. The future of autoimmune seizures/epilepsy care lies in leveraging these advancements to deliver personalized and effective treatments.

Epilepsy and Sexual Health

The intersection of epilepsy management with sexual health, HIV prevention, and gender-affirming care is highly nuanced. These clinical situations require inclusive, patient-centered approaches to better address the unique challenges faced by diverse populations living with epilepsy. There is an elevated prevalence of sexual health issues among PWE, particularly biological women, who experience higher rates of menstrual disorders, polycystic ovary syndrome (PCOS), and sexual dysfunction. EIASM contributes to these issues by reducing bioavailable testosterone and estradiol, resulting in hormonal imbalances. Valproate, for example, is associated with menstrual irregularities and hyperandrogenism. Medications like lamotrigine and levetiracetam generally have fewer sexual side effects, with lamotrigine even showing potential benefits in some cases. However, there is limited evidence with regard to newer ASM, and this calls for more research in this area.^43,44

Pre- and postexposure prophylaxis (PrEP/PEP) for HIV prevention is underutilized, especially in PWE. These preventive strategies are effective, yet their interaction with ASM requires careful consideration to avoid compromising the efficacy of either medication class or increasing adverse effects. Recent studies and public health guidelines have been reviewed separately in this journal to better educate neurologists about common regimens and how to best collaborate with care teams, to safely integrate PrEP/PEP into whole patient care. ⁴⁵

The importance of inclusive epilepsy care for transgender and gender diverse (TGD) patients undergoing gender-affirming treatment is highly relevant to our mission as doctors serving all segments of the population, particularly because this topic is not well covered in medical training.

We need to work toward a more holistic and inclusive approach to epilepsy care. By addressing sexual health, HIV prevention, and the needs of TGD individuals, clinicians can ensure equitable and compassionate care. Paramount to this goal is education, efficient collaboration, and fostering trust with patients to achieve better outcomes and quality of life for all people living with epilepsy.

Conclusion

Epilepsy care in the real world departs from merely controlling seizures. While seizure control remains the summum bonum for patients and their caregivers, managing epilepsy should account for the expected and the unexpected for overall improved survival and quality of life. Cardiovascular and metabolic diseases account for a high amount of co-morbidity in PWE. We discuss the interactions between cardiovascular drugs and antiseizure medications, emphasizing EIASM. A failure to account for those interactions could threaten optimal cardiovascular health. The expected also encompasses the importance of sexual health in people with epilepsy. Hormonal therapy, either for birth control or in transgender patients with epilepsy, deserves particular attention as the concomitant use of antiseizure medications can reduce their efficacy. In the field of sexual health, providers should strive to maintain antiretroviral drug efficacy in patients living with HIV and epilepsy. The unexpected happens. People living with epilepsy can suffer acute illnesses posing treatment challenges and interfering with their care. Infectious respiratory diseases were chosen to illustrate this owing to the high frequency of these conditions and their ambulatory and inpatient management. People with epilepsy may also develop seizures in the general context of autoimmune conditions. Specific immune-clinical syndromes need to be recognized for a prompt diagnosis and improved management and prognosis. The important caveat is that the onset of epilepsy in patients with autoimmune diseases, however, does not always imply an autoimmune mechanism.

This review's objective was to ignite conversations for a paradigm shift around epilepsy care. Treating people with epilepsy is a complex task that involves a deep understanding of patient comorbidities and a constant review of acute illnesses or new comorbidities. We hope to foster collaborations between epilepsy care providers, other providers, and pharmacists for improved epilepsy control, overall survival, and quality of life.